In this grant application we propose to continue a wide-ranging program of research on the molecular bases of the nature and specificity of DNA-protein interactions and on the structure and stability of the conformations of biological macromolecules. In both areas appropriate model studies will be combined with investigations of physiologically significant systems to further elucidate molecular mechanisms. In the area of DNA-protein interactions, we will continue to examine the interaction of the E. coli lac repressor with various small molecule inducers, as well as extending these studies to the interaction of uninduced and induced repressor with operator DNA. Both mutant and wild-type repressor will be used. The interaction between DNA and "melting-proteins" (proteins that bind preferentially to single-stranded DNA and thus lower the melting temperature of native DNA) will also be examined further. Chemical probes (e.g., formaldehyde) will be used to examine the "dynamic" structure of native DNA, as well as to serve as model "melting-protein" reagents. The interaction of real melting proteins with DNA will be studied as well. Research will also be continued on the base-pair specificity of the binding of small ligands (related to the functional groups of proteins) to native DNA, coupling these studies to manipulations of the solvent environment designed to alter the relative stability of the dA.T and dG.dC base pairs. Mechanistic and model studies will be continued and extended on the effects of solvent perturbants on the stability of molecular conformations. In one approach the thermodynamic and kinetic properties of fatty-acid-amide micelles as simple protein models will be examined. These micelles will then be made more "realistic" by the insertion of various paired and unpaired hydrogen-bonding and other polar groups into the non-polar interior in order to determine the effects of such functional groups on micellar stability and dynamics.